Basic and translational research has investigated the role of Nm23 in the regulation of tumor metastasis. Ten transfection studies have documented that overexpression of Nm23 in various tumor cell lines resulted in a 50-90% decrease in tumor metastatic potential in vivo. The biochemical mechanism whereby Nm23 suppresses metastatic potential is under investigation. We have previously reported that a histidine dependent protein phosphotransferase activity correlated with Nm23-H1 suppression of tumor cell motility, an aspect of metastasis. We identified a physiologic substrate for Nm23-H1 as a histidine kinase, the Kinase suppressor of ras (Ksr), which is a scaffold protein for the Map kinase pathway. Nm23-H1 phosphorylated serines 392 and 434 of Ksr. Transfection of breast carcinoma cells with wild type Nm23-H1 reduced Map kinase activation as compared to vector transfectant controls. Transfection of a histidine kinase-deficient Nm23-H1 resulted in high Map kinase levels, indicating that the histidine kinase activity of Nm23-H1 is responsible for modulation of signaling. We suggest the hypothesis that Nm23-H1 phosphorylation of Ksr results in altered scaffold function, reduced Map kinase signaling and reduced metastatic potential. Translational research on Nm23 proposes that elevation of Nm23 expression in micrometastatic or overtly metastatic breast or other carcinomas may limit colonization, motility and de-differentiation, with a clinical benefit. Analysis of the nm23-H1 promoter revealed a 400 bp region which controlled expression, and contained a cassette of transcription factors regulated by a glucocorticoid response element (GRE). Deletion studies showed that these sites were functional in regulating nm23-H1 transcription. Medroxyprogesterone acetate (MPA), an agonist for GR, androgen receptor and progesterone receptor, elevated Nm23-H1 expression of breast carcinoma cell lines in vitro. MPA acted via a post-transcriptional mechanism using the GR, at pharmacologic doses. We have conducted preclinical experiments to determine if MPA can halt metastatic colonization. Mice were injected iv with metastatic human MDA-MB-231 breast carcinoma cells, and permitted to develop micrometastases for one month. Mice were then randomized to control vehicle or MPA, the latter given in a one month induction and subsequent bimonthly maintenance dose. Mice receiving MPA had smaller metastatic colonies in the lung in two experiments. The data indicate that agents elevating metastsis suppressor gene expression may be effective against metastatic colonization.